/

2011 ()

Analysis for Repeated measures data 1

Survival analysis 37

SPSS () 73
 /

2011 ()
()

Analysis for Repeated measures data

( )

-1-
 2011 ()

Analysis
A l i ffor
Repeated measures data
( )

Contents
1. .
2. ?
3. Repeated measures ANOVA & Mixed model
4
4. Generalized estimating equation(GEE)

-3-
 /

1
1.
Ex)



(2 )

Paired t-test, or
Wilcoxons signed rank test

Design

2.
(Repeated measures data?)

: , , , .
: , , .

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 2011 ()

->

, (
)
(the measures within subjects are correlated)

Example1
(55 , 55 )
1, 3, 6, 9, 12

-5-
 /

1,
3, 6, 9, 12
( )
:

- (55, >55) , .
(Within subjects effect) (time effect) Main
effect
( )
- , (55 , )
.
(Between subjects
j effect) (age
g ggroup
p effect)

- (55 ,
) .
(Interaction
(I t ti effect(
ff t( ) )

Cf) , between-subject effect

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 2011 ()

(Interaction)
A


B


( A B
, A B
)
->
Ex)
(55 vs )
,

Blue line : 55
Red
d li
line : 55

3 6)
36)

10

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 /

time age(55, >55) age*time

11

example
p

12

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 2011 ()

3 &
3

<-
outcome

13

Example1
(55 , ) 1,
3, 6, 9, 12


( ) 5

14

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Complete data without missing (N

(N=16)
16)

Outcome variable (Continuous type)

:

Independent variables
: age(55 , ), time()

15

Green line: 55 , Blue line: 55

16

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 2011 ()

- , .
(Within subjects effect) (time effect)
Main
effect
- , (55 , ) ( )
.
(Between subjects effect) (age group effect)

- (55 ,
) . (Interaction effect( ) )

17

Method
h d:

Repeated measures ANOVA

18

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 /

Repeated measures ANOVA

- Outcome Normal Distribution( )

19

: OK

R
Repeated
t d measures ANOVA

th
then, check
h k


- ,
Greenhouse-Geisser

20

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 2011 ()

(Sphericity)
(S h i it )

:
(compound symmetry)
(equal
l variance)
i



Mauchly's Test of Sphericity

21

: O

Repeated
Greenhouse-
measures
Geisser
ANOVA

: X

22

- 13 -
 /

test

P-value > 0.05 ;

23

->
>

- ,
(P-value = 0.021)
- ) :
(55 , ) .
(P-value = 0.506) 24

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 2011 ()

- , (55 , )
(P-value=
. (P value 0
0.048)
048)

25

P-
P < 00.0
0 ; ,

26

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 /

- Pillai (trace)
- Wilks (lambda)
- g
Hotelling
-

SPSS default

27

.


->
>
Greenhouse-Geisser, Huyng-Feldt

28

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 2011 ()

() Stress data with missing (N

(N=21)
21)
Repeated measures ANOVA
Outcome variable
:

Independent variables
: age(55 , ), time()

29

Missing data


1 21 21 9
21.9 21 9
21.9 21 9
21.9
2 21 21.9 21.9 43.8
3 20 20.8 20.8 64.6

4 18 18.8 18.8 83.3

16 16. 16. 100.0
96 100 0
100.0 100 0
100.0

30

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 /

Repeated measures ANOVA

( : 16 (subjects without missing))

b
F
Pillai
590
.590 950a
3.950
3 4 000
4.000 11 000
11.000 .032
032

Wilks .410 3.950a 4.000 11.000 .032
1
Hotelling
1 436
1.436 950a
3.950
3 4 000
4.000 11 000
11.000 .032
032

Roy 1.436 3.950a 4.000 11.000 .032
Pillai
.284 1.090a 4.000 11.000 .408

Wilks .716 1.090a 4.000 11.000 .408
1 * age_
1 Hotelling
.396 1.090a 4.000 11.000 .408

Roy .396 1.090a 4.000 11.000 .408

31

Repeated d measures ANOVA

: complete data without missing

Reduced sample size
Selection bias

32

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 2011 ()

Example2
(more complicated data with missing)

How does craniofacial growth depend on testosteron

production?

Randomized experiment
p in which 50 male rats are
randomized to
- Control (15 rats) , Low does (18 rats),
High does (17 rats)
Treatment starts at the age
g of 45 days
y
Measurements
: everyy 10 days
y ; from dayy 50

33

Reponses
: distances between well defined points

34

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 /

Data

35

Missing (56%)

36

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Rat profiles

Rats
age(days)
g ( y )
ppattern

-> much variability among rats
- various intercept
- various
i slope
l ffor age
37

: Age(days) distance
(control, low dose, high dose)

38

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 /

Repeated measures ANOVA ?
->

Why?
- Missing due to dropout
- No consideration of variability among rats
- No consideration of various correlation structure
among time (age; days)

39

Not all measurements available due to dropout

: missing data

Much variabilityy among

g rats
: rat variability

Repeated measurements scheduled per rats.

: time points
->
(correlation structure)
( )

40

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Cf)
f Repeatedd measures ANOVA

- Include only subjects without missing observations

- () ( ,
)

41

Correlation structure
Correlation structure
Specifies how the observations within a
subject are related

Type
yp
Unstructured
Compound symmetry
Autoregressive AR(1)

42

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 /

Conpound symmetry( )
Any responses within the same subject has the
same correlation
Simple
p (1( parameter
p to estimate))

1

1
1

1

43

Autoregressive AR(1) (1 )
Correlation between responses depends on the
i t
interval
l off ti
time b
between
t responses
Farther apart responses => weaker correlation
Only
O l 1 parameter to estimate!
i !

1

1
2 1
3
2 1

44

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 2011 ()

Unstructured ()
All correlation
l ti coefficients
ffi i t ffree tto ttake
k any
value
E.g.,
Eg

1

0.3 1
0.1 0.5 1

0
0.05
05 0
0.2
2 0
0.4
4 1

45

()

Much variability between subjects

Missing data
Various correlation structure of repeated measurements

Mixed model

46

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 /

Mixed model
Mixed
d model
d l
- (fixed effect) (random effect)

(fixed effect)
- level

( level sampling
(,
level
)

(ex) age(55 , ), , , ,

47

(random effect)

level sampling
level fixed

(, level sampling

)

48

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 2011 ()

(ex1) medical center

1000 medical centers . ,
20 medical centers (100
level 20 level sampling), medical center

medical center effect
medical
center .

(ex2)
21 1, 3, 6, 9, 12
21
,

.

49

Example
l Analysis
l using mixed
d model
d l

Ex1) 900 5 medical center 180

, () center
,
,, center

Ex2) 100 1 (fixed level)

3 , 3 ,
,
,

50

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 /

In Stress Example1
p ((with missing)
g)
, ,
3 6,9,
3, 6 9

51

Patients profiles
100

80

60

40

20

0
1 2 3 4 5

Patient,
P i pattern
: due to Much variability between patients

Missing data
Various Correlation structure due to Repeated
p
measurements scheduled per patient
52

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(55 , ) .
(Interaction effect( ) )

Analysis using Mixed model

Random effect : patient effect

: due to Much variabilityy between p
patients

Fixed effect : age(55 , ), time

correlation structure : Ar(1)

53

Mixed model using g

AR(1) correlation structure

54

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 /

age*visit(interaction effect) ; P-value=0.493

:
(55 ,)

Age(55 , ) ; P-value = 0.056

:
, age
g stress

time (5 ) ; P-value = 0.014

: age , stress

55

age , stress
?

1 Reference
R f category
(1 3, 6, 9,
12 stress )

56

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 2011 ()

3 1 : P-value = 0.11557.. * 4 = 0.462

6 1 : P-value 0 01774 * 4 = 0.071
P l = 0.01774.. 0 071
9 1 : P-value = 0.00066.. * 4 = 0.003
12 1 : P-value
P l =0 00642 * 4 = 0.026
0.00642.. 0 026

(P-values are corrected by Bonferronis method due to

multiple testing)

57

: Bonferroni
Bonferroni correction
When
h Multiple
l l testing.

False positive error

(due to positive correlation between tests of comparisons)
->
P-value

HOW?
P-value * (# of multiple testings)

58

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4 Generalized estimating
4.
equation(GEE)
q ( )

59

outcome

outcome type
yp
- binary
- ordinal
- nominal

60

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Ex2) 1,
1 3,
3
6, 9, 12

Outcome type :

Outcome variable
: 1, 3, 6, 9, 12 (binary
data)

Independent variable
: (55 , )

61

62

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 /

:

(55 , ) .
(interaction effect() )

,
. ( main effect() )

,
.
( main effect()
( ) )

63

Analysis
l using Generalized
l d estimating equation
(GEE)

64

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 2011 ()

age*visit(interaction effect) ; P-value=0.009

(55
,)

65

Age(55 , ) ; P-value = 0.414

: , age stress

time (5 )
; P-value
l = 0.849
: age , stress

66

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Summary
1. Continuous outcome


2


Repeated measures ANOVA
case

(
(imputation)
p ) impute
p

Mixed model

. 67

2. Categoricall outcome
2


GEE(Generalized
GEE(G li d estimating
ti ti equation)
ti )

GLMM(G
GLMM(Generalized
li d Li
Linear mixed
i d model)
d l)
random effect fixed effect

68

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2011 ()
()

Survival analysis
( )

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 2011 ()

Survival analysis
( )

Contents

1. Survivall analysis
l ?
2. Survival data
3.
4.
5.
6. Event
7. Time dependent Cox regression model
8. More than one event

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 /

1 Survival analysis
1.

Data: Incomplete
l d
data

Incomplete?
-
<- censored data

Censoring : dont
d k
know survivall time exactly
l

Why censor ?
- Study ends
- Lost f/u
- Withdrawals

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 2011 ()

Time to event outcomes: censoring

Example
p of overall survival, over time

Time 0

Time to event outcomes: censoring

Example
p of overall survival, over time

Time 0 STUDY END

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 /

Time to event outcomes: censoring

Example
p of overall survival, over time

Time 0 STUDY END

Time to event outcomes: censoring

: More realistic clinical setting
Patients enter at various time points and are followed
until a common point in time

Time 0 STUDY END

8

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 2011 ()

Time to event outcomes: censoring

: More realistic clinical setting

Patients enter at various time points and are followed

until a common point in time

Ti
Time 0 STUDY END
9

Time to event outcomes: censoring

: even More realistic

wGGSGGGGTSGGGGG
GGGGG

Time 0 STUDY END

10

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 /

<-
Incomplete data

11

Incomplete Data

drop out withdrawal

12

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(, incomplete data)

13

( ) MACE(major
(ex) MACE( j adverse
d cardiac
di events)
t ) after
ft IIsolated
l t d
Aortic Valve Replacement in Patients with severe
Aortic Stenosis (A,
(A BB, C
C, D)

A (5mon)
B (24mon)
C (12mon)
D (
(9mon)
)

(: MACE, : non-MACE)

14

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 /

Subject MACE

A 5 MACE
at 5mon
B 24 Non-MACE

C 12 MACE
att 12mon
12
D 10 Non-MACE

15

Subject MACE 6
MACE
A 5 MACE MACE
at 5mon
B 24 Non-MACE Non-MACE

C 12 MACE Non-MACE
att 12mon
12
D 10 Non-MACE Non-MACE

MACEC rate
ate
at 5Mon
=
Complete
d t
data

16

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 2011 ()

Subject MACE 6 12
MACE MACE
A 5 MACE MACE MACE
at 5mon
B 24 Non-MACE Non-MACE Non-MACE

C 12 MACE Non-MACE MACE

att 12mon
12
D 9 Non-MACE Non-MACE ?

C rate
MACE ate MACE
C rate
ate
At 6Mon at 12Mon
= =?
Complete Incomplete
d t
data d t
data

17

Subject MACE 6 12 MACE free time

MACE MACE
A 5 MACE MACE MACE 5
at 5mon
B 24 Non-MACE Non-MACE Non-MACE ? (>24)

C 12 MACE Non-MACE MACE 12

att 12mon
12
D 9 Non-MACE Non-MACE ? ? (>9)

C rate
MACE ate MACE
C rate
ate MACE
C free
ee ttime
e
At 6Mon at 12Mon =?
= =?
Complete Incomplete Incomplete
d t
data d t
data d t
data

Subject
j B: censored at 24 mon after replacement
p
Subject D: censored at 9 mon after replacement
18

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 /

Survival analysis

19

2 Data
2.
(in Survival analysis)
y
Time to event

Event
(event ; (ex) event =1, censored=0)

20

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 2011 ()

E
Event
t () Ti
Time to
t eventt

Death
D h after
f O
Op
Recurrence after Tx -
Response after Tx -
Progression after first tx
-

21

Data
Ex) MACE(major adverse cardiac events) after Isolated Aortic Valve
Replacement in Patients with severe Aortic Stenosis (A, B, C, D)

Event = MACE after Isolated Aortic Valve Replacement

Time = Time to cardiac event after Isolated Aortic Valve
Replacement

22

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 /

id replacement Last F/U date

date

1 2008. 1. 21 2008. 6. 20
(MACE )

2 2007. 12. 4 2009. 12. 3

( F/U date)

3 2008. 3. 26 2009. 3.25

(MACE )

4 2008. 8. 31 2009. 06. 30

( F/U date)

23

id replacement Last F/U date Event Time

date (censoring )

1: MACE, (Last F/U date

0:censored Op date)

1 2008. 1. 21 2008. 6. 20 1 5
(MACE )
2 2007 12.
2007. 12 4 2009. 12.
2009 12 3 0 24
( F/U date)
3 2008. 3. 26 2009. 3.25 1 12
(MACE )
4 2008. 8. 31 2009. 05. 30 0 9
( F/U
/ date))

24

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 2011 ()

3
3.

- Kaplan-Meier
- Event

25

Kaplan Meier method

Kaplan-Meier
Ascending
A di order
d about
b observed
b d survival
i l time
i
Product-limit estimator of Kaplan-Meier method

Ex) 10 patients with lung cancer : After surgery, relapse (n=10)

(relapse: 3.0, 6.5, 10, 12, 15), (censored : 8.4, 4.0, 5.7, 10.0)
Time to Rank r (n-r)/(n-r+1) Survival rate
relapse
30
3.0 1 1 9/10 (9/10) = 0.9
09
4.0+ 2 - - -
5.7+ 3 - - -
6.5 4 4 6/7 (9/10)*(6/7) = 0.77
6.5 5 5 5/6 (9/10)*(6/7) *(5/6) = 0.64

15.0 10 10 0 0 26

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 /

4
4.

Log-rank
k test
-
( )
(: MACE . )

Breslow test
- Event

27

cross

-
Time dependent Cox regression ,
stratified Cox regression

28

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 2011 ()

E ) Multi-vessel
Ex) M li l di
disease
non-ST-elevation
ST l i myocardial
di l
infarction single vessel multi
vessel MACE free curve

Variable :
G
Group (M
(Multi
l i vessel=1,
l 1 single
i l vessel=2)
l 2)
Time to MACE(month)
Status(MACE ; MACE=1,
MACE=1 censored=0)

29

MACE free rate Kaplan-Meier

MACE free rate MACE free rate SE

30

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 /

=4.767Mo , S(4.767)=0.922 , se=0.031

=5.057Mo , S(5.057)=0.906 , se=0.034

31

5M MACE free
5Mo f rate ?

..
Group=1
: 5Mo MACE free rate = 92%
0.922

0.906
..

time=5.0

time=4 767
time=4.767 time=5 057
time=5.057

32

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5Mo MACE free Curve

33

Group
p MACE free curve
-> Log-rank test

Results

P-value = <.001 ;
Group MACE free curve

34

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 /

5
5.

: t .

t S1(t) S2(t)
,

|Z|
p value ( SE1 SE2 S1(t) S2(t) )
p-value

35

E ) multi-vessel
Ex) li l di
disease
non ST elevation
l i myocardial
di l
infarction single vessel multi
vessel 5 MACE free rate

Variable :
G
Group (M
(Multi
l i vessel=1,
l 1 single
i l vessel=2)
l 2)
Time to MACE(month)
Status(MACE ; MACE=1,
MACE=1 censored=0)

36

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 2011 ()

Group=1 (multi vessel)

: 5Mo - MACE free rate = 0.922, se=0.031

37

~~~

~~~

~~~ Group=2
G 2 ((single
i l vessel)
l)
: 5Mo MACE free rate = 0.634, se=0.033

38

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 /

5 MACE free rate

: 5 MACE free rate .

g
group=1:
p 5Mo MACE free rate=0.922 (SE=0.031)
group=2: 5Mo MACE free rate=0.634 (SE=0.033)

- =NORMDIST(6.361,0,1,TRUE)
enter <.999
- P-value = 2*(1-<.999)=<.0001
5Mo MACE free rate SE Z-test

39

6. Event
( )

Ex) Multi-vessel disease non ST elevation myocardial

infarction single g vessel , age g
() Lesion type MACE(major adverse cardiac events)

Variable :
Age(year)
g y
lesion type (1, 2, 3, 4)
Time to MACE(month)
Status(MACE(major j adverse
d cardiac
di events); MACE=1, censored=0)
d

40

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 2011 ()

41

Analysis
l using Cox proportionall hazards
h d model
d l
(MACE ( ))

:
- MACE
( )
(=Proportional hazard(PH) )

42

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 /

Result

B)
B al B) 95.0

lesion 36.98
36 98 3.00
3 00 0.000
0 000
lesion1) -2.86 1.01 8.02 1.00 0.000 0.06 0.01 0.1
lesion2) -1.38 0.28 23.8 1.00 0.000 0.25 0.15 0.
lesion3) -0
0.82
82 0 20
0.20 16 9
16.9 1 00
1.00 0 000
0.000 0
0. 0 30
0.30 0 65
0.65
age 0.03 0.01 12.00 1.00 0.000 1.03 1.01 1.05

Lesion 4 MACE .

(P-value = <.001)

llesion(1):
i (1) 1 vs 4 ; P-value
P l = < 0.001
0 001 X 3 = <.001
001
lesion(2): 2 vs 4 ; P-value = < 0.001 X 3 = <.001
lesion(3): 3 vs 4 ; P-value = < 0.001 X 3 = <.001
(P-values were corrected by Bonferronis method due to multiple testing)
43

Hazard ratio(HR)
HR is
i the
h ratio
i off two h
hazard
d rates.

A measure of association between the outcome variable and an

independent variable in Cox regression

The hazard ratio is expressed in terms of an exponential of a

regression coefficient in Cox regression model.

If independent variable with more than two categories

(ex; lesion (1, 2, 3, 4)), calculate more than one HR
-> (ex; 1 2, 1 3, 1 4, 2 3, 2 4, 3 4)

Cf) Hazard
H d rate
t isi the
th instaneous
i t rate
t for
f eventt occurrence. (difficult
(diffi lt
for practical interpretation)
44

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 2011 ()

Ex)) Hazard ratio for lesion ((2 vs 4))

Hazard ratio(HR)
= (hazard in lesion 2) / (hazard in lesion 4)

If lesion(II vs IV) is a risk factor

(hazard in lesion 2) (hazard in lesion 4) HR 1

If lesion(II vs IV) is not a risk factor

(hazard in lesion 2) = (hazard in lesion 4) HR = 1

45

Note 1: HR OR, HR RR (Relative Risk)

N t 2
Note 2: HR P-value
P l

Note 3: P>0.05
P>0 05 95% CI for HR includes HR
HR=1
1.0
0

Note 4: ,
event

( ) lesion
(ex) l i 2 vs 4 ,

lesion 2 event
)

46

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 /

Cf)
f
RR = the ratio of risks
OR = the ratio of odds (logistic regression)
HR = the ratio of hazard rates (Cox regression)

47

Proportional hazard(PH)
check
(1) Graphical
h l approach
h
- Survival graph
- log (-log
( log (survival)) graph

(2) Statistical test

48

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 2011 ()

lesion
- PH check: Graphical approach

lesion Survival graph

49

lesion log(-log (survival)) graph

50

- 63 -
 /

lesion
- PH check; Statistical test
Schoenfeld
h f ld residual
d l (Harrell and
d Lee(1986))

Step1
partial residual Cox regression

Step2
Event=1 time partial
residual

51

lesion(1) lesion(2) lesion(3) age

-.966** -.558** -.226* -.103

Spearman r
ho
Month ( .000 .000 .011 .251

N 125 125 125 125

52

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 2011 ()

PH check
L i MACE
Lesion

Cox regression

Time-dependent Cox regression analysis

53

7 Time dependent Cox

7. Co regression

Exp(B) 95.0%
95 0%
B Wald Exp(B) CI

age 0.03 0.01 10.87 1.00 0.00 1.03 1.01 1.05
lesion 31.57 3.00 0.00
lesion(1) -4.13 2.37 3.04 1.00 0.08 0.02 0.00 1.67
lesion(2) -2
2.70
70 0 62
0.62 18 81
18.81 1 00
1.00 0 00
0.00 0 07
0.07 0 02
0.02 0 23
0.23
lesion(3) -1.60 0.37 18.39 1.00 0.00 0.20 0.10 0.42

T_COV_*lesion 10.15 3.00 0.02

T_COV_*lesion(1) 0.27 0.33 0.65 1.00 0.42 1.31 0.68 2.51

T_COV_*lesion(2) 0.29 0.10 7.84 1.00 0.01 1.34 1.09 1.64

_ _ ( ) 0.20
T_COV_*lesion(3) 0.08 6.72 1.00 0.01 1.22 1.05 1.42

54

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 /

Age , lesion MACE

lesion .
(P-value =0.02)

- Age , lesion 2 MACE

lesion 4 .

(P-value =0.01*3=0.03)

- Age , lesion 3 MACE

lesion 4 .
(P-value =0.01*3=0.03)

(P-values
(P values were corrected by Bonferroni
Bonferroniss method due
to multiple testing)

55

HR for
f lesion
l i (2 vs 4(=ref))
4( f)) over the
th follow-time
f ll ti
time HR
1 0.089815 2.5
2 0.120032
3 0.160414 2
4 0.214381
5 0.286505 1.5
6 0.382893
7 0.511709 1
8 0.683861
9 0.913931 0.5
10 1.221403
11 1.632316 0
12 2.181472 1 2 3 4 5 6 7 8 9 10 11 12

<-
HR(t) = exp(-2.7
exp( 2 7*(1
(1-0)+0.29
0)+0 29* (1
(1*tt-0
0*t))
t)) = exp(
exp(-2.7+0.29t)
2 7+0 29t)

56

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number status month lesion age

lesion=4 lesion=2 , 70 0 9.5 2 56.4
event 36 0 99
9.9 2 56 4
56.4
99 0 10.5 2 48.5
31 1 10.5 2 41.6
51 1 10.5 2 52.1
93 0 10.7 2 36.5
34 0 10.8 2 52.1
45 0 11.0 2 41.8
24 1 11 2
11.2 2 44 5
44.5
25 0 11.3 2 45.1
29 0 12.3 2 63.9
43 0 12.5 2 48.9

number status month lesion age

85 1 9.2 4 47.2
21 0 94
9.4 4 64 2
64.2
112 1 9.4 4 55.5
11 1 10.3 4 53.7
83 0 11.1 4 56.0
71 0 11.5 4 48.8
42 0 12.2 4 33.7
40 0 12.2 4 46.7
32 0 12 4
12.4 4 54 0
54.0

57

8 More than one event

8. e ent
()

More than one event may be considered

58

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 /

Recurrent event survival analysis

Recurrent events
Outcome events that may occur more than once over the
follow-up time for a given subject.

Ex1) Repeated heart attacks-coronary patients

p relapse
Ex2) Multiple p from remission leukemia p
patients
Ex3) Recurrence of tumors - bladder cancer patients

59

Competing Risks survival analysis

(Competing Risk)
-


. (2 )
- ,
.

Cf) This situation contrasts with the topic of recurrent event

(subjects could experience more than one event of a given
type)

60

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 2011 ()

Allogeneic hematopoietic stem cell transplantation

(HSCT) Study
- event of interest : disease relapse
-> BUT, disease relapse mortality related to complications
of transplantation

61

Disease relapse
l competing risk
k transplant
l related
l d
morality (TRM) ?

62

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 /

Analysis
l using Competing risk
k

63

() KM vs CR

64

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 2011 ()

1
Site (1=Upper T 2=Mid T 3=Lower T 4=Main) survival curve

65

site=2 2 .
site=2
death



.

->
>

- ,

-,

descriptive

66

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 /

Summary
G
General
l method
h d S
Survival
i ld data analysis
l i
Summary of data Descriptive statistics Descriptive statistics
mean, variance Survival rate
median, inter quartile Median survival time
range (IQR)
Tests for K independent Parametric method Parametric method
samples t-test Likelihood ratio test(LRT)
One-way ANOVA
p
Nonparametric method
Nonparametric Log-rank test
method
Mann-Whitney test
Kruskal-Wallis test
Regression Multiple linear Cox regression
regression
g Time dependent
p Cox
Logistic regression regression
67

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 /

2011 ()

SPSS ()

- 73 -
 2011 ()

SPSS
SPSS

(
))
OzV~GaGpitGzwzzGzGX`PG

y
- Repeated measures ANOVA (Ex1-1)
- Analysis using Mixed model (Ex1
(Ex1-2)
2)
- Analysis using Generalized estimating
q
equation (GEE)
( ) ((Ex2))

y
- Survival rate estimation & Log-rank test(Ex3-1)
- Cox regression analysis (Ex3-2)
- Time dependent Cox regression analysis
(Ex3-2)
2

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 /

Example 1-
1 -1
(Repeated measures ANOVA)

Ex1) (55, >55) 1,

3, 6, 9, 12

id age age_1 stress_score.1 stress_score.2 stress_score.3 stress_score.4 stress_score.5
62 57 1.00 81 78 60 77 78
2,083 56 1.00 67 77 70 77 79
2,166 57 1.00 50 62 70 77 80
3,504 58 1.00 77 80 73 77 70
4 755
4,755 53 0 00
0.00 76 60 70 71 73
6,039 61 1.00 66 70 75 80 70
8,523 55 0.00 80 88 77 75 80
8,792 56 1.00 55 69 73 73 70
11,973 55 0.00 69 67 70 77 80
12 655
12,655 53 0 00
0.00 75 77 75 80 88
13,156 57 1.00 68 70 75 77 60
13,161 55 0.00 75 77 80 88 70
14,922 56 1.00 67 70 76 77 80
15,229 57 1.00 69 67 80 81 88
,
17,743 55 0.00 81 84 85 80 77
20,232 54 0.00 73 70 77 80 77

:
- ((55
, ) . ( )
- , .
- , .

- 76 -
 2011 ()

N=16 (complete data without missing)

Outcome variable (Continuous type)

:

Independent variable
: age(55 , ), time()

y Method :

Repeated measures ANOVA

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 /

Method in SPSS

> >

- 78 -
 2011 ()

XW

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 /

XX

N
.00 7
age_1
1 00
1.00 9

- 80 -
 2011 ()

y test

y P-value > 0.05 ;

->

- ,

(P-value = 0.021)
-
(55 , ) .

(P-value = 0.506)

- 81 -
 /

- , (55 , )
(P-value=
. (P value= 0.048)
0 048)

Example 1-
1-2 (Mixed model)
Ex1) (55, >55) 1,
3, 6, 9, 12

X]

- 82 -
 2011 ()

N=21 (data with missing)

Outcome variable
:

Independent variable
: age(55 , ), time()

Random effect : patient effect

: due to Much variability
y between patients
p

Fixed effect : age(55 , ), time

correlation structure : Ar(1)

- 83 -
 /

Analysis using Mixed model

X`

YW

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 2011 ()

> >

YX

(
( )
)

- 85 -
 /

YZ

Y[

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 2011 ()

Y\

Y]

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 /

Y^

Model Checking

y Residual plot
: to detect any outliers or a general lack
normality

Y_

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 2011 ()

Y`

ZW

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 /

Explore the residual distribution

> >

ZX

ZY

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 2011 ()

ZZ

Z[

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 /

Example 2 (GEE)

Ex2) 1, 3, 6, 9, 12

:

(55 ,
,)
)

Outcome variable
: 1,
1 3,
3 6,
6 9,
9 12

Independent
depe de t variable
a ab e
: (55 , ), time

Analysis using Generalized estimating

equation (GEE)

- 92 -
 2011 ()

Z^

Analysis using GEE

> >

Z_

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 /

Z`

[W

- 94 -
 2011 ()

[X

[Y

- 95 -
 /

[Z

96 100 0%
100.0%

0 .0%

96 100 0%
100.0%

id 21

- visit 5

21

2

5

- 96 -
 2011 ()

Tests of odel ffects

Type III

Source Wald Chi-Square df Sig.

(Intercept) 3 182
3.182 1 .074
074

age_1 .668 1 .414

visit 1.372 4 .849

age_1 visit 13.96 4 .009

Survival analysis

- 97 -
 /

Example 3-
3-1

Ex) Multi-vessel disease non-ST-elevation myocardial

infarction single vessel multi
vessel MACE free curve

Variable :
Group (Multi vessel=1, single vessel=2)
Time to MACE(month)
(MACE ; MACE=1, =

MACE free rate Kaplan

Kaplan--Meier

[_

- 98 -
 2011 ()

[`

MACE free curve

\W

- 99 -
 /

Results MACE free MACE free rate

rate
t SE

=4.767Mo , S(4.767)=0.922 , se=0.031

=5.057Mo , S(5.057)=0.906 , se=0.034

\Y

- 100 -
 2011 ()

\Z

Group MACE free curve

-> Log-rank
L k test

- 101 -
 /

Results

\\

Example 3-
3-2

Ex) Multi-vessel disease non ST elevation myocardial

infarction single vessel , age
() Lesion type MACE(major adverse cardiac
events)

Variable :
Age(year)
lesion type (1, 2, 3, 4)
Time to MACE(month)
Status(MACE(major adverse cardiac events);
MACE=1,censored=0)

- 102 -
 2011 ()

\^

Analysis using Cox proportional hazards

model
(MACE ( ))

:
- MACE .

- 103 -
 /

Analysis using Cox proportional

h
hazards
d modeld l
> > Cox

\`

]W

- 104 -
 2011 ()

]X

]Y

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 /

Lesion 4 MACE .
(P-value = <.001)

lesion(1): 1 vs 4 ; P-value = < 0.001 X 3 = <.001

lesion(2): 2 vs 4 ; P-value = < 0.001 X 3 = <.001
lesion(3): 3 vs 4 ; P-value
P value = < 0.001
0 001 X 3 = <.001
< 001
(P-values were corrected by Bonferronis method due to multiple testing)

PH(Proportional hazard) check

(1) Graphical approach

- Survival graph
- log (-log (survival)) graph

(2) Statistical test

][

- 106 -
 2011 ()

lesion
- PH check: Graphical approach
> > Cox >

]\

lesion
lesion Survival graph

]]

- 107 -
 /

lesion
lesion
log(--log (survival)) graph
log(

]^

lesion
- PH check; Statistical test

y Schoenfeld residual (Harrel and Lee(1986))

Step1
partial residual Cox regression

Step2
Event=1 time partial
residual

]_

- 108 -
 2011 ()

Schoenfeld residual method

> > Cox >

]`

^W

- 109 -
 /

> >

^X

^Y

- 110 -
 2011 ()

lesion(1) lesion(2) lesion(3) age

-.966** -.558** -.226* -.103

Spearman r
Month ( .000 .000 .011 .251
ho

N 125 125 125 125

PH check

y Lesion MACE

Cox regression

Time-dependent Cox regression analysis

- 111 -
 /

Time dependent Cox regression

> > Cox

^\

^]

- 112 -
 2011 ()

^^

^_

- 113 -
 /

^`

Exp(B) 95.0%
B Wald Exp(B) CI

age 0.03 0.01 10.87 1.00 0.00 1.03 1.01 1.05
lesion 31.57 3.00 0.00
lesion(1) -4.13 2.37 3.04 1.00 0.08 0.02 0.00 1.67
lesion(2) -2.70 0.62 18.81 1.00 0.00 0.07 0.02 0.23
lesion(3) -1.60 0.37 18.39 1.00 0.00 0.20 0.10 0.42

T_COV_*lesion 10.15 3.00 0.02

0 27
0.27 0 33
0.33 0 65
0.65 1 00
1.00 0 42
0.42 1 31
1.31 0 68
0.68 2 51
2.51
T_COV_*lesion(1)

0.29 0.10 7.84 1.00 0.01 1.34 1.09 1.64

T_COV_*lesion(2)

0.20 0.08 6.72 1.00 0.01 1.22 1.05 1.42

T_COV_*lesion(3)

80

- 114 -
 2011 ()

y Age , lesion MACE

lesion .
(P-value =0.02)

- Age , lesion 2 MACE

lesion 4 .

(P-value =0.01*3=0.03)

- Age , lesion 3 MACE

lesion 4 .
(P-value =0.01*3=0.03)
=0 01*3=0 03)

(P-values were corrected by Bonferronis method due

to multiple testing)

- 115 -
 /

Example 1
1--1

_Z

Example 1
1--2

_[

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 2011 ()

Example 2

_\

_]

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 /

Example 3
3--1

_^

__

- 118 -
 2011 ()

_`

`W

- 119 -
 /

`X

Example 3
3--2

`Y

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 2011 ()

`Z

`[

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 /

`\

- 122 -